The present invention relates to novel peptides having antagonistic activity to endothelin receptors. These novel peptides are useful as prophylactic and therapeutic drugs for hypertension, cardiac or cerebral circulatory diseases, renal diseases and asthma, and to the production thereof. The present invention further relates to the use thereof.
Endothelin (ET) is a vasoconstrictive peptide composed of 21 amino acid residues. Endothelin was isolated from the culture supernatant of the endothelial cells of porcine aortas. Its structure was determined by M. Yanagisawa et al. in 1988 [M. Yanagisawa et al., Nature 332, 411-415 (1988)]. More recently, the research on genes coding for endothelin revealed the presence of peptides similar to endothelin in structure. These peptides are named endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), respectively, and their structures are as follows: ##STR2## (All of the amino acids constituting ET-1, ET-2 and ET-3 take the L-form.) [Inoue et al., Proc. Natl. Acad. Sci. U.S.A. 86, 2863-2867 (1989)]
The above-mentioned peptides of the endothelin family exist in vivo and have vasopressor activity. For this reason, these peptides are anticipated to be intrinsic factors responsible for the control of circulatory systems, and deduced to be related to hypertension, cardiac or cerebral circulatory diseases (for example, cardiac infarction) and renal diseases (for example, acute renal insufficiency). In addition, these peptides also have bronchial smooth muscle constrictor activity, and therefore deduced to be related to asthma.